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Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways
Open accessAbstract
Insulin induces and dietary n-3 PUFAs suppress hepatic de novo lipogenesis by controlling sterol-regulatory element binding protein-1 nuclear abundance (nSREBP-1). Our goal was to define the mechanisms involved in this regulatory process. Insulin treatment of rat primary hepatocytes rapidly augments nSREBP-1 and mRNA(SREBP-1c) while suppressing mRNA(Insig-2) but not mRNA(Insig-1). These events are preceded by rapid but transient increases in Akt and Erk phosphorylation. Removal of insulin from hepatocytes leads to a rapid decline in nSREBP-1 [half-time (T1/2) approximately 10 h] that is abrogated by inhibitors of 26S proteasomal degradation. 22:6,n-3, the major n-3 PUFA accumulating in livers of fish oil-fed rats, suppresses hepatocyte levels of nSREBP-1, mRNA(SREBP-1c), and mRNA(Insig-2) but modestly and transiently induces mRNA(Insig-1). More importantly, 22:6,n-3 accelerates the disappearance of hepatocyte nSREBP-1 (T1/2 approximately 4 h) through a 26S proteasome-dependent process. 22:6,n-3 has minimal effects on microsomal SREBP-1 and sterol-regulatory element binding protein cleavage-activating protein or nuclear SREBP-2. 22:6,n-3 transiently inhibits insulin-induced Akt phosphorylation but induces Erk phosphorylation. Inhibitors of Erk phosphorylation, but not overexpressed constitutively active Akt, rapidly attenuate 22:6,n-3 suppression of nSREBP-1. Thus, 22:6,n-3 suppresses hepatocyte nSREBP-1 through 26S proteasome- and Erk-dependent pathways. These studies reveal a novel mechanism for n-3 PUFA regulation of hepatocyte nSREBP-1 and lipid metabolism.
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“Beyond enhancing β-oxidation, n-3 PUFAs concurrently suppress de novo lipogenesis by inhibiting the expression and maturation of SREBP-1, and by reducing the activity of ChREBP, thereby curbing hepatic glycolysis and lipid synthesis.34–37”
From The Impact of Omega-3 Fatty Acids on Triglyceride Levels in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-Analysis of Randomized Controlled Trials with Subgroup Analysis by Diabetes Status (2026) · cites this paper as [34]
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“In addition, n-3 FAs lead to intracellular degradation of apo B, which may be a result of decreased triglyceride availability or autophagic destruction of apo B via post-Golgi oxidation, 90 thereby diminishing the assembly of VLDL particles in the hepatocyte and decreasing VLDL secretion.91,92”
From Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association (2019) · cites this paper as [90]
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Metadata
- Authors
- Botolin, D., Wang, Y., Christian, B., & Jump, D. B.
- Affiliations
- Michigan State University (US)
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 47
- Issue
- 1
- Pages
- 181-192
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC2764363
- OpenAlex
- W2164098551
- Cited by
- 162
- References
- 40
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 8 · 2012: 10
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Agriculture
- National Institutes of Health
- Cooperative State Research, Education, and Extension Service
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK043220)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- docosahexaenoic acid, omega-3 fatty acids, SREBP1, INSIG2, INSIG1, 26S proteasome, ERK1/2 phosphorylation, Akt phosphorylation, insulin signaling, hepatocytes, hepatic de novo lipogenesis, SREBP-1c, SREBP2, lipid metabolism
- MeSH terms
- Animals, Base Sequence, Cell Nucleus, Dietary Fats, Docosahexaenoic Acids, Insulin, Male, Membrane Proteins, Protease Inhibitors, RNA, Messenger, Rats, Sprague-Dawley, MAP Kinase Signaling System, Hepatocytes, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Rats, Sterol Regulatory Element Binding Protein 1, Proteasome Inhibitors
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